Neurodevelopmental disorders are generally categorized as disorders associated with changes in early brain development. These typically exhibit themselves as behavioral and cognitive alterations in sensory and motor systems, speech, and language. Particular reference is made to autism spectrum disorder, cerebral palsy, Rett syndrome, Angelman syndrome, Williams syndrome, and Smith-Magenis syndrome.
Rett syndrome (RTT), originally termed cerebroatrophic hyperammonemia, is a rare genetic postnatal neurological disorder of the grey matter of the brain that almost exclusively affects females but has also been found in male patients. The clinical features include small hands and feet and a deceleration of the rate of head growth (including microcephaly in some). Repetitive stereotyped hand movements, such as wringing and/or repeatedly putting hands into the mouth, are also noted. People with Rett syndrome are prone to gastrointestinal disorders and up to 80% have seizures. They typically have no verbal skills, and about 50% of affected individuals do not walk. Scoliosis, growth failure, and constipation are very common and can be problematic.
The signs of this disorder are most easily confused with those of Angelman syndrome, cerebral palsy, and autism. Rett syndrome occurs in approximately 1:10,000 live female births in all geographies, and across all races and ethnicities.
Without being bound by any particular theory it is believed that Rett syndrome is caused by mutations in the gene MECP2 located on the X chromosome (which is involved in transcriptional silencing and epigenetic regulation of methylated DNA), and can arise sporadically or from germline mutations. Reportedly, in less than 10% of RTT cases, mutations in the genes CDKL5 or FOXG1 have also been found to resemble it. Rett syndrome is initially diagnosed by clinical observation, but the diagnosis is definitive when there is a genetic defect in the MECP2 gene.
Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73, AV2-73, or A2-73) is a compound which is believed to bind to muscarinic acetylcholine and sigma-1 receptors with affinities in the low micromolar range. It has been reported that A2-73 showed neuroprotective potential against amyloid toxicity in mice. In particular, A2-73 has been reported as attenuating oxidative stress, caspases induction, cellular loss and learning and memory deficits observed in mice one week after the i.v. injection of an oligomeric preparation of amyloid β25-35 peptide (Aβ25-35) (Villard et al., J. Psychopharmacol. 2011). More recently, it has been reported that A2-73 blocked the Aβ25-35-induced P-Akt decrease and P-GSK-3β increase, indicating activation of the PI3K neuroprotective pathway (Lahmy et al., Neuropsychopharmacology, 2013). In the dose-range tested, A2-73 attenuated the hyperphosphorylation of Tau on physiological epitopes (AT-8 antibody clone) and on pathological epitopes (AT-100 clone). A2-73 also has been reported decreasing the Aβ25-35-induced endogenous Aβ1-42 seeding.
It has been reported that neurodevelopmental disorders respond to N-methyl-D-aspartate receptor (NMDAR) antagonists and combination therapy. Reference is made to NMDAR antagonists selected from the group consisting of Amantadine, AZD6765, Dextrallorphan, Dextromethorphan, Dextrorphan, Diphenidine, Dizocilpine (MK-801), Ethanol, Eticyclidine, Gacyclidine, Ibogaine, Memantine, Methoxetamine, Nitrous oxide, Phencyclidine, Rolicyclidine, Tenocyclidine, Methoxydine, Tiletamine, Xenon, Neramexane, Eliprodil, Etoxadrol, Dexoxadrol, WMS-2539, NEFA, Delucemine, 8A-PDHQ, Aptiganel, HU-211, Remacemide, Rhynchophylline, Ketamine, 1-Aminocyclopropanecarboxylic acid (ACPC), 7-Chlorokynurenate′ DCKA (5,7-dichlorokynurenic acid), Kynurenic acid, Lacosamide, L-phenylalanine, Neurotransmitters, Psychedelics, Long-term potentiation, and NMDA.
Reference is made to the following publications. These publications, and all publications cited herein, are incorporated by reference in their entirety:    1. “Rett Syndrome Fact Sheet. NIH Publication No. 09-4863”. National Institute of Neurological Disorders and Stroke (NINDS). November 2009.    2. Guy et al., (2007). “Reversal of Neurological Defects in a Mouse Model of Rett Syndrome.” Science 315 (5815): 1143-7. doi:10.1126/science.1138389. PMID 17289941.    3. Trappe et al, “MECP2 Mutations in Sporadic Cases of Rett Syndrome Are Almost Exclusively of Paternal Origin.” The American Journal of Human Genetics 68 (5): 1093-101.    4. Fitzgerald et al (1990). “Rett syndrome and associated movement disorders”. Movement Disorders 5 (3): 195-202.    5. Ricceri et al (2008). “Mouse models of Rett syndrome: From behavioural phenotyping to preclinical evaluation of new therapeutic approaches”. Behavioural Pharmacology 19 (5-6): 501-17. doi:10.1097/FBP.0b013e32830c3645. PMID 18690105.    6. Lombardi, et al, “MECP2 disorders: from the clinic to mice and back,” J Clin Invest. 2015 Aug. 3; 125(8):2914-23. doi: 10.1172/JCI78167. Epub 2015 Aug. 3. Review.    7. Pohodich et al, “Rett syndrome: disruption of epigenetic control of postnatal neurological functions.” Hum Mol Genet. 2015 Oct. 15; 24(R1): Epub 2015 Jun. 9.    8. Lotan et al, Rett Syndrome: Therapeutic Interventions (Disability Studies) 1st Ed (Nova Science Publishers, Inc 2011) PMID: 26060191.    9. U.S. Pat. No. 9,180,106 (Vamvakides) “Sigma receptors ligands with anti-apoptotic and/or pro-apoptotic properties, over cellular mechanisms, exhibiting prototypical cytoprotective and also anti-cancer activity.”    10. Mallon et al, “EuroPhenome and EMPReSS: online mouse phenotyping resource,” Nucleic Acids Res. 2008 January; 36(Database issue):D715-8. Epub 2007 Sep. 28.    11. Morgan et al, “EuroPhenome: a repository for high-throughput mouse phenotyping data,”. Nucleic Acids Res. 2010 January; 38(Database issue):D577-85. doi: 10.1093/nar/gkp1007. Epub 2009 Nov. 23.    12. Tropea et al., “Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice”. Proceedings of the National Academy of Sciences 106 (6): 2029-34. (2009),    13. Tan et al., “Pharmacological therapies for Angelman syndrome,” Wien Med Wochenschr. 2016 Jan. 12. [Epub ahead of print]    14. US Pub. No 2015/0152410 to Kreig et al., entitled “Compositions And Methods For Modulating Mecp2 Expression.”    15. US Pub. No 2015/0265554 to Roux et al, “Treatment of MeCP-2 Associated Disorders.”    16. U.S. Pat. No. 7,994,127 to Sur et al., Treatment of Rett Syndrome And Other
Disorders.